Efficacy and safety of veliparib plus chemotherapy for the treatment of lung cancer: A systematic review of clinical trials

Background As a poly-ADP ribose polymerase (PARP) inhibitor, veliparib has been identified as a potential therapeutic agent for lung cancer. The present study aimed to conduct a systematic review of clinical trials investigating the efficacy and safety of veliparib for treating lung cancer. Methods PubMed, Scopus, the Web of Science, and Google Scholar were systematically searched up to October 30, 2022. Only randomized controlled trials (RCTs) evaluating the efficacy or safety of veliparib in the treatment of lung cancer patients were included. Studies were excluded if they were not RCTs, enrolled healthy participants or patients with conditions other than lung cancer, or investigated therapeutic approaches other than veliparib. The Cochrane risk-of-bias tool was used for quality assessment. Results The seven RCTs (n = 2188) showed that patients treated with a combination of veliparib and chemotherapy had a significantly higher risk of adverse events, when compared to the control arm. There was no statistically significant difference in overall survival (OS) between those treated with veliparib plus chemotherapy and those receiving the standard therapies. Only two trials demonstrated an improvement in progression-free survival (PFS), and only one study found an increase in objective response rate (ORR). Furthermore, adding veliparib to standard chemotherapy showed no benefit in extending the duration of response (DoR) in any of the studies. Conclusions Only a small number of studies have found veliparib to be effective, in terms of improved OS, PFS, and ORR, while the majority of studies found no benefit for veliparib over standard treatment.


Introduction
Lung cancer has evolved from a rare and obscure disease to the second most common form of cancer, with the highest rate of cancer-related mortality and one of the most dismal 5-year survival rates of all cancers [1].Lung cancer is histologically and clinically classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which individually account for approximately 15% and 85% of lung cancer histologic subtypes, respectively, with the latter being further subcategorized into lung adenocarcinoma and squamous cell lung carcinoma [2].Despite tremendous breakthroughs in surgical and ablative strategies, as well as chemotherapy and radiation therapy, the relative 5-year survival rates for NSCLC and SCLC remain roughly 26% and 7%, respectively, due to the scarcity of early diagnostic strategies and the poor responsiveness of currently used treatment regimens [3,4].This highlights the need for research into more individualized therapies.The discovery of actionable oncogenic mutations has markedly improved the treatment of many cancers, as highlighted by the progression and clinical application of targeted therapeutics hampering driver mutations [5].Epigenetic and expression-level profiling methods have substantially enhanced our insight into the implications of the DNA-damage repair (DDR) pathway deficits and the accompanying genomic instability in tumor development and progression [6,7].
Unlike normal cells, continuous therapeutic use of chemotherapy and/or radiation along with endogenous sources comparatively predisposes tumor cells to DNA insults, while the repairing systems are likely to be disrupted in these cells, resulting in the accumulation of mutations that drive tumor progression [8].DDR signaling triggers the transcription and enhanced expression of repair proteins, notably poly-(ADP)-ribose polymerase (PARP), which regulate multiple DDR pathways [9].Since these pathways are essential for the repair of DNA double-strand breaks during the S and G2 phases of the cell cycle, inhibiting the PARP enzyme tends to increase PARP immobilization at DNA single-strand breaks and the conversion of single-strand breaks to double-strand breaks, entailing homologous recombination repair for replication forks to overcome this DNA lesion [10].According to the synthetic lethality theory, blocking both the single-strand break and the homologous recombination repair mechanisms concurrently might synergistically reduce cell viability, rendering PARP, as a fundamental component of the single-strand break, a viable therapeutic target for homologous recombination-deficient tumors [11].Similarly, patients with homologous recombination-proficient tumors, including SCLC, can benefit from PARP inhibitors, but their effectiveness is not as striking as it is in homologous recombination-deficit tumors [12].Furthermore, DDR mutations, such as ATM, PTEN, MRE11, and FANCA mutations, have been found in a large proportion of lung cancer patients, as well as BRCA1/2 mutations in 5% of patients, justifying the administration of PARP inhibitors to lung cancer patients [13,14].
Veliparib (ABT-888) is an oral selective PARP 1/2 inhibitor that has shown anticancer activity in both homologous recombination-deficit and homologous recombination-proficient tumors [15].According to preclinical studies, veliparib sensitizes tumor cells to DNA-damaging therapies, such as chemotherapy and radiation [16].Platinum-based chemotherapy agents, including cisplatin and carboplatin, and alkylating agents such as temozolomide, are known to have therapeutic effects in lung cancer by damaging the DNA in cancer cells and inhibiting their viability and proliferation.By combining veliparib with these chemotherapy agents, the synergistic effects may enhance the therapeutic efficacy of the chemotherapy [17].Thus, we aimed to conduct a systematic review of the literature to evaluate the efficacy and safety of veliparib in combination with chemotherapy for the treatment of lung cancer.

Methods
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 guidelines [18].

Literature search
PubMed, Scopus, and the Web of Science databases were searched, without any time or language constraints, up to October 30, 2022.In order to find additional relevant studies, the first 30 pages of the Google Scholar search engine were manually searched [19].Furthermore, backward and forward citation searches of all included studies were performed.The search terms used included a comprehensive combination of terms related to lung neoplasms and veliparib: ("Veliparib" OR "ABT-888" OR "NSC 737664") AND ("Lung Neoplasms" OR "Pulmonary Blastoma" OR "Lung tumor" OR "Lung adenocarcinoma") (S1 Table ).

Study selection
Studies identified through the systematic search were all exported to EndNote 20 software, and any duplicates were removed.Two researchers independently screened each publication's title and abstract using the inclusion criteria.The same two researchers then independently examined the entire texts of all studies that passed the first screening, and any disagreements were resolved via discussion or consultation with a third researcher.Only randomized controlled trials (RCTs) that evaluated the efficacy or safety of veliparib treatment in lung cancer patients, regardless of their cancer type or stage, were included in this study.Moreover, there was no minimum number of study participants for inclusion in the current study.Conversely, studies that did not meet these inclusion criteria, such as those that involved healthy individuals or patients with conditions other than lung cancer, or investigated therapeutic approaches that did not include veliparib, were excluded.

Data extraction
Two researchers independently performed the data extraction, using a uniform data extraction sheet in Microsoft Office Excel.The following data were extracted: 1) the study characteristics, including title, first author's name, publication year, country of study, phase of the trial, the median length of the treatment, and the median follow-up duration; 2) the characteristics of the enrolled participants, including study population, sample size, age range, sex ratio, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status, cancer ascertainment, and characteristics; and 3) the main results and safety or efficacy outcomes of the studies.All extracted data were double-checked by two other authors.

Quality assessment
The risk of bias and quality of the included studies were independently assessed by two researchers using version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB2) [20].The RoB2 rates each study a low, high, or unclear risk of bias (some concerns) across five domains: randomization process, deviations from the intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results.Any discrepancies between the two researchers were settled via discussion or consultation with a third researcher.The risk of bias graphs were created in R software, using the robvis package [21].

Study selection
In the first step, there were 537 articles identified, of which 125 were duplicates and were removed.After screening the titles and abstracts of the remaining 412 reports, another 390 reports were excluded, with the remaining 22 reports being further assessed for eligibility.Ten reports were excluded due to the absence of a control arm [22][23][24][25][26][27][28][29][30][31], two studies had insufficient data [32,33], one study was excluded as the comparison between the intervention and control arms was inappropriate [34], one study was not a clinical trial [35], and one study was a reanalysis of a previous study [36].After the exclusion of 15 studies, the remaining seven studies met the eligibility criteria and were included in our review [37][38][39][40][41][42][43]

Study characteristics
There were 2188 patients enrolled in the seven studies, which were conducted in more than 37 countries across the globe.In one study (Argiris et al.) there were two phases, the first of which was conducted without a control arm [37].The included studies consisted of one open-label [43], one single-blind [37], and five remaining studies were all double-blind [38][39][40][41][42].The sample size of the included studies ranged from 21 to 970 participants, while the follow-up duration ranged from 10-12 weeks to four years.The median age of the participants was from 60 to 70 years and the majority of the participants were male (72.0%).In addition, most of the participants were current or former smokers (Tables 1 and 2).Each of these studies included at least one treatment arm, which involved combination therapy with veliparib, and they all detailed the simultaneous chemotherapy regimens and cycles that were employed.Carboplatin plus paclitaxel was the most commonly utilized concurrent chemotherapy treatment, followed by carboplatin plus etoposide, cisplatin plus etoposide, and the temozolomide chemotherapy regimen (Table 1).The characteristics of the included participants are summarized in Table 2.

Assessment of risk of bias
All of the included studies were found to have a high overall risk of bias, with a high risk of bias being noted in the measurement of outcomes in all studies.However, all studies had a low risk of bias in the missing outcome data.In addition, the majority of the included studies [37][38][39][40][41][42] (all but one) [43] were rated as having a low risk of bias in the selection of the reported results (Fig 2 and S2 Table).

Efficacy
Survival outcomes were the primary endpoints in the included studies.All of these studies reported progression-free survival (PFS), which only improved in two of the studies [38,39].The PFS was similar between the chemotherapy plus veliparib and the chemotherapy alone arms in the five remaining studies.The study conducted by Byers et al. included three arms: veliparib plus chemotherapy followed by veliparib maintenance (i.e., veliparib throughout), veliparib plus chemotherapy followed by a placebo (i.e., veliparib combination-only), or a placebo plus chemotherapy followed by a placebo (i.e., control arm).As the authors of the study concluded, there was a statistically significant difference in PFS only between the veliparib throughout and control arm (p = 0.06; level of significant: p<0.2), but PFS did not differ between the veliparib combination-only and the control arm (p = 0.92) [38].
The overall survival (OS) was reported in all included studies, but only Ramalingam et al. 2021 [42] found a statistically significant difference between the treatment and control arms.Furthermore, objective response rate (ORR) and the duration of response (DoR) were the other outcomes that were measured in all and five [38,[40][41][42][43] of the included studies, respectively.The ORR only favored the intervention arm in one study [40].Moreover, adding veliparib to a conventional chemotherapy regimen did not increase the DoR in any of the studies (Table 3).
In two studies [42,43], tissue samples were taken to evaluate the level of the LP52 biomarker, and a subsequent subgroup analysis was done based on the presence or absence of this biomarker.Although in the studies by Govindan et al. [43] and Ramalingam et al. 2021 [42] the participants in the two arms had statistically similar PFS and OS, respectively, those who had positive LP52 biomarkers showed improved efficacy.

Safety
All studies defined adverse events (AEs) using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0.Moreover, treatment- related AEs were reported in both the intervention and control arms across all studies.Hematologic AEs, including anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and febrile neutropenia were the most commonly reported treatment-related AEs, followed by non-hematologic AEs such as fatigue, nausea, vomiting, dizziness, dermatologic AEs (e.g., alopecia and dry skin), myalgia, arthralgia, constipation, diarrhea, and dyspnea.The most common AEs reported in the control arms were fatigue, nausea, constipation, anemia, neutropenia, and thrombocytopenia.Most of the deaths were not related to the received treatments.Four cases of grade-5 treatment-related AEs were reported in two of the studies [37,38] (Table 4).

Discussion
The present qualitative synthesis of the seven RCTs showed that in most studies there were no statistically significant differences between those who received veliparib and the controls, in terms of OS, PFS, ORR, and DoR.Regarding the safety profile, the frequency of any grade and severe grade AEs were generally higher in the intervention group containing veliparib, than among the controls.
The use of PARP inhibitors alone, or in combination with other regimes, can be used for SCLC management for repairing DNA damage, inhibiting DNA damage, or activating the immune system [44].Most of the previous studies using PARP inhibitors to treat SCLC used olaparib or veliparib and demonstrated modest efficacy [45].The efficacy measures that were most frequently reported in the included studies were OR, PFS, and ORR.The meta-analysis by Bao and colleagues on PARP inhibitors in cancer therapy showed that PARP inhibitors significantly increased the PFS (HR: 0.67; 95% CI: 0.50-0.90)[46].However, PARP inhibitors had no significant effect on PFS (HR: 0.98; 95% CI: 0.83-1.15)or OS (HR: 1.00; 95% CI: 0.76-1.31)among lung cancer patients [46].Another recent meta-analysis on the efficacy of PARP inhibitors for treating solid tumors found that PARP inhibitors did not improve the OS and ORR for NSCLC and SCLC (p<0.05), while it only improved PFS in SCLC (HR: 0.77; 95% CI: 0.63-0.95)[47].The subgroup analysis by type of PARP inhibitor showed that veliparib can significantly improve the PFS (HR: 0.82; 95% CI: 0.80-0.97),while it did not reveal any statistically significant improvement in ORR (HR: 1.04; 95% CI: 0.89-1.22)or OR (HR: 0.93; 95% CI: 0.83-1.05)[47].Similarly, we found that only two studies reported improvements in PFS and  only one study reported improvements in OS or ORR.One of the limitations of meta-analyses is that the analyses are likely to lead to insignificant results when there are a small number of primary studies available.Therefore, the meta-analyses should be re-run in the future with a larger number of studies.The efficacy and safety of PARP inhibitors have also been investigated for other types of cancer.The results of a network meta-analysis showed significantly improved PFS (HR: 0.37; 95% CI: 0.20-0.69)and ORR (HR: 7.07; 95% CI: 1.83-27.32)for veliparib + chemotherapy, compared with chemotherapy alone, while it was not significant in terms of pathologic complete response (HR: 2.06; 95% CI: 0.84-5.07)[48].Moreover, PARP inhibitors have also been used to treat prostate cancer, although veliparib has been found to be the least potent of the PARPs evaluated [49].For ovarian cancer, PARP inhibitors significantly improved PFS (HR: 0.51; 95% CI: 0.40-0.65),when compared with a placebo or chemotherapy alone [50].The differences between the findings on the efficacy of PARP inhibitors, in particular veliparib, for different solid tumors may be as a result of variations in the inclusion/exclusion criteria, types of analyses used, and the number of studies included.The descriptive results on the frequency of AEs in patients with lung cancer revealed an overall higher frequency of any grade and severe grade AEs in those receiving veliparib plus chemotherapy, compared with those receiving standard chemotherapy.Interestingly, a study by Bao et al. on the safety of PARP inhibitors in treating cancers, reported a decreased risk of asthenia (RR: 0.34; 95% CI: 0.14-0.82)and an increased risk of neutropenia (RR: 1.14; 95% CI: 1.01-1.29),while there were no differences between the intervention and control groups for other respiratory, gastrointestinal, and hematologic AEs [46].A systematic review of trials among patients with advanced ovarian cancer showed that those receiving PARP inhibitors had a significantly higher risk of hematologic and gastrointestinal AEs [51].Overall, it seems that patients with different types of cancer, in particular lung cancer, who receive PARP inhibitors might have a higher frequency of any grade and severe grade AEs, compared with those on standard chemotherapy, although this should be further investigated in future RCTs and meta-analyses.
The studies included in our systematic review received low-quality ratings, using the last version of the Cochrane RoB2 tool.In contrast, a systematic review and meta-analysis on PARP inhibitors in solid tumors, which included 29 studies, showed a low risk of bias in most domains and the only domain with a high risk of bias was performance bias, due to the inclusion of open-label studies [47].These differences can be explained by the use of different quality rating tools (version 1 vs. version 2 of the Cochrane risk of bias assessment) and the evaluation of different studies [47].A study by Chang et al., which evaluated the efficacy and safety of PARP inhibitors for treating breast cancer, also used the Cochrane RoB2 for quality assessment [52].They found that two of the six trials had a high risk of bias, which was due to the missing outcome data domain [52].In addition, in a meta-analysis of studies using PARP inhibitors as maintenance therapy for ovarian cancer, a low risk of bias was found in all six of the included RCTs using the Cochrane RoB2 [53].The high risk of bias among the included studies in our systematic review was mostly due to the measurement of the outcome domain.Therefore, it is of great importance to conduct further high-quality RCTs for treating lung cancer patients with veliparib, with specific attention to the deviation from intended interventions and the measurement of outcomes.The high risk of bias in the studies included in our systematic review should be noted in the interpretation and generalization of the study outcomes.
The safety and efficacy of PARP inhibitors have been previously evaluated in patients with several different types of cancer [46,47].However, to the best of our knowledge, this is the first study that has specifically focused on veliparib in patients with lung cancer.However, the current systematic review has several limitations that should be taken into consideration when interpreting the results.Firstly, the number of included studies is relatively small, so the findings should be interpreted with some caution.Secondly, due to the heterogeneity between the studies, especially in terms of the interventions and subjects in the control group, a meta-analysis and sub-group analysis could not be performed.Thirdly, we searched three online databases, in addition to grey literature, but there is still the possibility that some eligible studies were missed.Fourthly, all of the included studies had a high risk of bias, which also highlights the need to interpret the data with some caution.Fifthly, due to the limited number of studies, we could not evaluate selection or publication bias.In addition, although we mentioned the demographic and clinical characteristics of participants, there might be other confounding variables that were not evaluated.Finally, this research can be seen as a guide to further robust research on the clinical use of veliparib as a PARP inhibitor in patients with lung cancer.

Conclusion
Although veliparib has been shown to improve the OS, PFS, and ORR in a small number of studies, for the majority there were no significant differences between the intervention and control arms.In addition, veliparib plus chemotherapy showed a higher rate of AEs than did standard chemotherapy for lung cancer.There is a critical need for additional high-quality clinical trials on the safety and efficacy of veliparib in lung cancer patients.Upon completion of these studies, a meta-analysis would also be recommended.